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The role of total plasma cell-free DNA (cfDNA) in lung cancer (LC) screening with low-dose computed tomography (LDCT) is uncertain. We hypothesized that cfDNA could support differentiation between malignant and benign nodules observed in LDCT. The baseline cfDNA was measured in 137 subjects of the ITALUNG trial, including 29 subjects with screen-detected LC (17 prevalent and 12 incident) and 108 subjects with benign nodules. The predictive capability of baseline cfDNA to differentiate malignant and benign nodules was compared to that of Lung-RADS classification and Brock score at initial LDCT (iLDCT). Subjects with prevalent LC showed both well-discriminating radiological characteristics of the malignant nodule (16 of 17 were classified as Lung-RADS 4) and markedly increased cfDNA (mean 18.8 ng/mL). The mean diameters and Brock scores of malignant nodules at iLDCT in subjects who were diagnosed with incident LC were not different from those of benign nodules. However, 75% (9/12) of subjects with incident LC showed a baseline cfDNA ≥ 3.15 ng/mL, compared to 34% (37/108) of subjects with benign nodules ( p = 0.006). Moreover, baseline cfDNA was correlated ( p = 0.001) with tumor growth, measured with volume doubling time. In conclusion, increased baseline cfDNA may help to differentiate subjects with malignant and benign nodules at LDCT.

Background: Cervical cancer is a major health problem in Latin America. In 2019, the Italian Agency for Development Cooperation (La Paz regional site) conducted a pilot study to estimate the prevalence of high-risk human papillomavirus (HPV) and the feasibility of HPV screening in Bolivia through self-sampling and portable and transportable laboratory instruments for HPV testing in urban and rural areas., Methods: Women aged 20-65 years from La Paz (urban area), Toro Toro (rural area), and Acasio (rural area) were enrolled in local public health centers between Dec 1, 2019, and June 30, 2021. Self-sampling was carried out with the Viba-Brush system (Rovers, Oss, Netherlands) and samples were preserved in ThinPrep containers (Hologic Corporation, San Diego, CA, USA). The GeneXpert system (Cepheid, Sunnyvale, CA, USA) for high-risk HPV testing detects HPV E6 and E7 DNA via real-time PCR in a mobile system of easy execution requiring minimal manual intervention. The system provides results in about 1 h. The hr- HPV prevalence data, overall and partial genotyping, were analyzed considering the following age groups: 20-34, 35-44, and 45-65 years old., Findings: 2168 women were enrolled: 614 (28.3%) in La Paz, 743 (34.3%) in Toro Toro, and 811 (37.4%) in Acasio. Only one sample was collected from each participant. 2043 (94.2%) of 2168 samples were adequate for HPV testing. 255 (12.5%) samples were positive for high-risk HPV. Comparing the urban area (La Paz) versus rural combined areas (Acasio+Toro Toro), using a logistic model, the HPV total rate was statistically significantly higher in the city of La Paz (15.0% vs 11.4%; OR:1.37;95% CI: 1.04-1.80). Furthermore, the HPV prevalence was declining by age, and the urban/rural odds ratio was 1.50; (95% IC 1.13-19). The overall HPV 16 positivity was 2.7% (55/2043) and for HPV 18/45 was 1.8% (37/2043) without any statistically significant differences between the three BHU enrolling centers. Only the prevalence of HPV group '39/56/66/68' was significantly higher in La Paz (p<0,001) in comparison to Acasio and Toro Toro., Interpretation: The total and age-adjusted prevalence of high-risk HPV infection in rural and urban areas in Bolivia, as measured with a validated test for screening, is similar to that observed in Europe and the USA. Our study shows that a screening protocol for HPV testing with self-sampling would be feasible in urban and rural areas in Bolivia, and that the reported high occurrence of cervical cancer in Bolivia is not related to a higher rate of high-risk HPV infections. Carrying out HPV tests locally avoids the issues associated with transportation and storage of the collected material and allows the participant to wait in the clinic for the test result, overcoming the very long response time for screening test in Bolivia., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Carozzi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: (a) To estimate the risk of recurrent cervical intraepithelial neoplasia, grade 2/3 or worse (CIN2+/CIN3+), lesions within 5 years of follow-up in human papillomavirus-negative/human papillomavirus-positive cohorts; (b) to assess whether certain risk factors can predict the recurrence of CIN2+/CIN3+ lesions; and (c) to provide recommendations for follow-up after treatment of cervical intraepithelial neoplasia, grade 2/3 to prevent cervical cancer ., Setting: Organized cervical cancer screening programme in Central Italy., Methods: We included 1063 consecutive first excisional treatments performed between 2006 and 2014 for screening-detected cervical intraepithelial neoplasia, grade 2/3 lesions among women aged 25-65. The study population was divided into two groups according to the human papillomavirus test results performed 6 months after treatment: Human papillomavirus-negative and human papillomavirus-positive cohorts. The 5-year risk of developing cervical intraepithelial neoplasia, grade 2/3 or worse (CIN2+/CIN3+) was estimated using the Kaplan-Meier method and the Cox regression model., Results: Among 829 human papillomavirus-negative and 234 human papillomavirus-positive women, six (0.72%; three cervical intraepithelial neoplasia, grade 2, three cervical intraepithelial neoplasia, grade 3) and 45 (19.2%; 15 cervical intraepithelial neoplasia, grade 2, 30 cervical intraepithelial neoplasia, grade 3), respectively, developed CIN2+ recurrence within 5 years of follow-up. The cumulative risks for CIN2+ and CIN3+ were 0.9% (95% confidence interval: 0.4%-2.0%) and 0.5% (95% confidence interval: 0.1%-1.4%), respectively, for the human papillomavirus-negative cohort, and 24.8% (95% confidence interval: 18.5%-32.7%) and 16.9% (95% confidence interval: 11.4%-24.5%), respectively, for the human papillomavirus-positive cohort. Risk factors associated with increased risk of recurrence were both margins positive for the human papillomavirus-negative cohort, and positive margins, cervical intraepithelial neoplasia, grade 3 lesions, high-grade cytology and high viral load for the human papillomavirus-positive cohort., Conclusions: Human papillomavirus testing can identify women at increased risk of recurrence and this supports a recommendation for its use in the post-treatment follow-up of cervical intraepithelial neoplasia, grade 2/3 lesions., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To evaluate the association between human papillomavirus vaccination status and participation in cervical cancer screening (at age 25) by the first cohorts of girls who were offered vaccination at the age of 15 to 16 years in Italy., Methods: Women born in 1993, 1994 and 1995 were invited to participate in cervical cancer screening between 2018 and 2020. We report participation in screening by vaccination status in three large areas, Florence province, Piedmont region and Savona province, where the Consensus Project was carried out. The relative risk of participation among vaccinated (≥2 doses) and unvaccinated women was estimated. Odds ratios (OR) of participation by vaccination status were estimated by logistic regression, adjusted by birthplace and birth cohort., Results: Overall, 34,993 women were invited for screening: 13,006 (37.2%) participated and 10,062 of these agreed to participate in the Consensus intervention study. Among the invited women and screening participants, vaccinated women were 51.0% and 60.6%, respectively. Comparing vaccinated and unvaccinated women, the adjusted OR of screening participation was 1.80 (95% confidence interval (CI): 1.72-1.89), 2.17 (95% CI: 1.94-2.42), 1.59 (95% CI: 1.50-1.68) and 1.15 (95% CI: 0.86-1.54) for overall, Florence, Piedmont and Savona, respectively. About 33% of the invited women were unvaccinated and did not participate in screening: 25.8%, 59.5% and 64.2% of women born in Italy, in high migration pressure countries and in advanced development countries, respectively., Conclusions: Screening participation was higher among vaccinated than unvaccinated women. Active policies are needed to reduce inequalities, targeting the unscreened and unvaccinated population, particularly non-native women, to accelerate cervical cancer elimination in Italy.

The ITALUNG trial started in 2004 and compared lung cancer (LC) and other-causes mortality in 55-69 years-aged smokers and ex-smokers who were randomized to four annual chest low-dose CT (LDCT) or usual care. ITALUNG showed a lower LC and cardiovascular mortality in the screened subjects after 13 years of follow-up, especially in women, and produced many ancillary studies. They included recruitment results of a population-based mimicking approach, development of software for computer-aided diagnosis (CAD) and lung nodules volumetry, LDCT assessment of pulmonary emphysema and coronary artery calcifications (CAC) and their relevance to long-term mortality, results of a smoking-cessation intervention, assessment of the radiations dose associated with screening LDCT, and the results of biomarkers assays. Moreover, ITALUNG data indicated that screen-detected LCs are mostly already present at baseline LDCT, can present as lung cancer associated with cystic airspaces, and can be multiple. However, several issues of LC screening are still unaddressed. They include the annual vs. biennial pace of LDCT, choice between opportunistic or population-based recruitment. and between uni or multi-centre screening, implementation of CAD-assisted reading, containment of false positive and negative LDCT results, incorporation of emphysema. and CAC quantification in models of personalized LC and mortality risk, validation of ultra-LDCT acquisitions, optimization of the smoking-cessation intervention. and prospective validation of the biomarkers.

Background: SARS-CoV-2 pandemic represented a huge challenge for national health systems worldwide. Pooling nasopharyngeal (NP) swabs seems to be a promising strategy, saving time and resources, but it could reduce the sensitivity of the RT-PCR and exacerbate samples management in terms of automation and tracing. In this study, taking advantage of the routine implementation of a screening plan on health workers, we evaluated the feasibility of pool testing for SARS-CoV-2 infection diagnosis in the presence of low viral load samples., Method: Pools were prepared with an automated instrument, mixing 4, 6 or 20 NP specimens, including one, two or none positive samples. Ct values of positive samples were on average about 35 for the four genes analyzed., Results: The overall sensitivity of 4-samples and 6-samples pools was 93.1 and 90.0%, respectively. Focussing on pools including one sample with Ct value ≥35 for all analyzed genes, sensitivity decreased to 77.8 and 75.0% for 4- and 6-samples, respectively; pools including two positive samples, resulted positive in any size as well as pools including positive samples with Ct values <35., Conclusion: Pool testing strategy should account the balance between cost-effectiveness, dilution effect and prevalence of the infection. Our study demonstrated the good performances in terms of sensitivity and saving resources of pool testing mixing 4 or 6 samples, even including low viral load specimens, in a real screening context possibly affected by prevalence fluctuation. In conclusion, pool testing strategy represents an efficient and resources saving surveillance and tracing tool, especially in specific context like schools, even for monitoring changes in prevalence associated to vaccination campaign.

Disruptions to cancer screening services have been experienced in most settings as a consequence of the COVID-19 pandemic. Ideally, programmes would resolve backlogs by temporarily expanding capacity; however, in practice, this is often not possible. We aim to inform the deliberations of decision makers in high-income settings regarding their cervical cancer screening policy response. We caution against performance measures that rely solely on restoring testing volumes to pre-pandemic levels because they will be less effective at mitigating excess cancer diagnoses than will targeted measures. These measures might exacerbate pre-existing inequalities in accessing cervical screening by disregarding the risk profile of the individuals attending. Modelling of cervical screening outcomes before and during the pandemic supports risk-based strategies as the most effective way for screening services to recover. The degree to which screening is organised will determine the feasibility of deploying some risk-based strategies, but implementation of age-based risk stratification should be universally feasible., Competing Interests: Declaration of interests MR reports funding from Hologic and grants from Public Health England, outside of the submitted work. MAS reports grants from the National Health and Medical Research Council and the Cancer Institute New South Wales. SJBH reports grants from National Cancer Centre Japan. SP reports being a member of the Board of Directors for the Canadian Agency for Drugs and Technologies in Health. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Facing the SARS-CoV-2 epidemic requires intensive testing on the population to early identify and isolate infected subjects. During the first emergency phase of the epidemic, RT-qPCR on nasopharyngeal (NP) swabs, which is the most reliable technique to detect ongoing infections, exhibited limitations due to availability of reagents and budget constraints. This stressed the need to develop screening procedures that require fewer resources and are suitable to be extended to larger portions of the population. RT-qPCR on pooled samples from individual NP swabs seems to be a promising technique to improve surveillance. We performed preliminary experimental analyses aimed to investigate the performance of pool testing on samples with low viral load and we evaluated through Monte Carlo (MC) simulations alternative screening protocols based on sample pooling, tailored to contexts characterized by different infection prevalence. We focused on the role of pool size and the opportunity to develop strategies that take advantage of natural clustering structures in the population, e.g. families, school classes, hospital rooms. Despite the use of a limited number of specimens, our results suggest that, while high viral load samples seem to be detectable even in a pool with 29 negative samples, positive specimens with low viral load may be masked by the negative samples, unless smaller pools are used. The results of MC simulations confirm that pool testing is useful in contexts where the infection prevalence is low. The gain of pool testing in saving resources can be very high, and can be optimized by selecting appropriate group sizes. Exploiting natural groups makes the definition of larger pools convenient and potentially overcomes the issue of low viral load samples by increasing the probability of identifying more than one positive in the same pool., Competing Interests: The authors have declared that no competing interests exist.

Background: The objective of this study was to describe the determinants of adequacy and positivity of the p16/Ki-67 assay in a human papillomavirus (HPV)-positive screening population enrolled within the New Technologies for Cervical Cancer 2 (NTCC2) study., Methods: ThinPrep slides were immunostained for p16/Ki-67; each slide had 3 reports from different laboratories. The authors included population-related, sampling-related/staining-related, and interpretation-related variables in the analyses. Adequacy and positivity proportions were stratified by variables of interest. Univariate and multivariate logistic models were used to identify determinants of adequacy and positivity., Results: In total, 3100 consecutive HPV-positive cases were analyzed. Because every slide was interpreted by 3 centers, 9300 reports were obtained, including 905 (9.7%) that were inadequate and 2632 (28.3%) that were positive. The percentage of cases in which all 3 reports were inadequate increased with increasing age of the women and with inadequate cytology. The highest percentage of adequacy in all 3 reports and of cases with all 3 reports positive was observed in specimens from women who had grade ≥2 cervical intraepithelial neoplasia (CIN2+), atypical squamous cells of undetermined significance or more severe (ASC-US+) cytology, or mRNA positivity. The number of inadequate reports was significantly associated with increasing age, inadequate cytology, mRNA negativity, and scant cellularity. A positive p16/Ki-67 report was associated with an ASC-US+ result and with a positive mRNA result in cases both with and without CIN2+ but was associated with an HPV type 16 and/or 18 infection only in CIN2+ cases. The presence of CIN2+ was strongly associated with dual staining positivity., Conclusions: The interpretation of p16/Ki-67 results may be influenced by several different variables, all of which are part of the steps in the procedure, and by the characteristics of the screened population., (© 2020 American Cancer Society.)

Objectives: Overdiagnosis in low-dose computed tomography randomized screening trials varies from 0 to 67%. The National Lung Screening Trial (extended follow-up) and ITALUNG (Italian Lung Cancer Screening Trial) have reported cumulative incidence estimates at long-term follow-up showing low or no overdiagnosis. The Danish Lung Cancer Screening Trial attributed the high overdiagnosis estimate to a likely selection for risk of the active arm. Here, we applied a method already used in benefit and overdiagnosis assessments to compute the long-term survival rates in the ITALUNG arms in order to confirm incidence-excess method assessment., Methods: Subjects in the active arm were invited for four screening rounds, while controls were in usual care. Follow-up was extended to 11.3 years. Kaplan-Meyer 5- and 10-year survivals of "resected and early" (stage I or II and resected) and "unresected or late" (stage III or IV or not resected or unclassified) lung cancer cases were compared between arms., Results: The updated ITALUNG control arm cumulative incidence rate was lower than in the active arm, but this was not statistically significant (RR: 0.89; 95% CI: 0.67-1.18). A compensatory drop of late cases was observed after baseline screening. The proportion of "resected and early" cases was 38% and 19%, in the active and control arms, respectively. The 10-year survival rates were 64% and 60% in the active and control arms, respectively ( p  = 0.689). The five-year survival rates for "unresected or late" cases were 10% and 7% in the active and control arms, respectively ( p  = 0.679)., Conclusions: This long-term survival analysis, by prognostic categories, concluded against the long-term risk of overdiagnosis and contributed to revealing how screening works.

Background: Changes in smoking habits and predictors of smoking cessation were examined in the randomized ITALUNG lung cancer screening trial., Methods: In three centers, eligible smokers or ex-smokers (55-69 years, ≥20 pack-years in the last 10 years) were randomized to receive annual invitation for low-dose computed tomography for 4 years or usual care. At invitation, subjects received written information for a free smoking cessation program. Quitting outcome was assessed at year 4., Results: Among participants who completed baseline assessments and year 4 screening, higher quitting (20.8% vs. 16.7%, p = .029) and lower relapse (6.41% vs. 7.56%, p = .50) rates were observed in the active screening group as compared to the usual-care control group. Corresponding figures in the intention-to-treat analysis were as follows: 16.04% versus 14.64% (p = .059) and 4.88% versus 6.43% (p = .26). Quitting smoking was significantly associated to male gender, lower pack-years, and having pulmonary nodules at baseline. Center-specific analyses showed a threefold statistically significant higher probability to quit associated with participating in the smoking cessation program. A subsample of smokers of the scan group from one center showed higher quitting rates over 12-month follow-up as compared to matched controls from the general population who underwent the same smoking cessation program., Conclusions: Consistently with previous reports, in the ITALUNG trial, screened subjects showed significantly higher quit rates than controls, and higher quit rates were associated with both the presence of pulmonary nodules and participating in a smoking cessation program. Maximal effect on quitting outcome was observed with the participation in the smoking cessation program., Implications: Participating in lung cancer screening promotes smoking cessation. An effective "teachable moment" may be achieved when the smoking cessation intervention is structured as integral part of the screening clinical visits and conducted by a dedicated team of health care professionals. Standardized guidelines for smoking cessation interventions in lung cancer screening are needed., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.)

Background: p16/Ki-67 dual staining is a candidate biomarker for triaging human papillomavirus (HPV)-positive women. Reproducibility is needed for adopting a test for screening. This study assessed interlaboratory reproducibility in HPV-positive women., Methods: All women positive for HPV from the Italian New Technologies for Cervical Cancer 2 study, were included in this study. ThinPrep slides were immunostained for p16/Ki-67 in 4 laboratories and were interpreted in 7 laboratories. Each slide had 3 reports from different laboratories. Slides were classified as valuable or inadequate, and valuable slides were classified as positive (at least 1 double-stained cell) or negative. Interlaboratory reproducibility was evaluated with κ values., Results: Overall, we obtained 9300 reports for 3100 cases; 905 reports (9.7%) were inadequate. The overall adequacy concordance was poor (κ = 0.224; 95% confidence interval [CI], 0.183-0.263). The overall positivity concordance was moderate (κ = 0.583; 95% CI, 0.556-0.610). Of the 176 cervical intraepithelial neoplasia 2+ (CIN-2+) lesions found in HPV DNA-positive women, 158 had a valid result: 107 were positive in all 3 reports (sensitivity for CIN-2+, 67.7%; 95% CI, 59.8%-74.9%), 23 were positive in 2 reports (sensitivity of the majority report, 82.3%; 95% CI, 75.4%-87.9%), and 15 were positive in 1 report (sensitivity of at least 1 positive result, 91.8%; 95% CI, 86.3%-95.5%). Thirteen CIN-2+ cases were negative in all 3 reports. The overall positivity concordance in CIN-2+ samples was κ = 0.487 (95% CI, 0.429-0.534), whereas in the non-CIN-2+ samples, it was κ = 0.558 (95% CI, 0.528-0.588)., Conclusions: The p16/Ki-67 assay showed poor reproducibility for adequacy and good reproducibility for positivity comparable to that of cervical cytology. Nevertheless, the low reproducibility does not affect the sensitivity for CIN-2+., (© 2020 American Cancer Society.)

Objectives: In the ITALUNG lung cancer screening trial after 9.3 years of follow-up we observed an unexpected significant decrease of cardiovascular (CV) mortality in subjects invited for low-dose CT (LDCT) screening as compared to controls undergoing usual care. Herein we extended the mortality follow-up and analyzed the potential factors underlying such a decrease., Materials and Methods: The following factors were assessed in screenes and controls: burden of CV disease at baseline, changes in smoking habits, use of CV drugs and frequency of planned vascular procedures after randomisation. Moreover, in the screenes we evaluated inclusion of presence of coronary artery calcification (CAC) in the LDCT report form that was transmitted to the participant and his/her General Practitioner., Results: The 2-years extension of follow-up confirmed a significant decrease of CV mortality in the subjects of the active group compared to control subjects (15.6 vs 34.0 per 10,000; p = 0.001) that was not observed in the drops-out of the active group. None of the explaining factors we considered significantly differed between active and control group. However, the subjects of the active group with reported CAC experienced a not significantly lower CV mortality and showed a significantly higher use of CV drugs and frequency of planned vascular procedures than the control group., Conclusions: LDCT screening for lung cancer offers the opportunity for detection of CAC that is an important CV risk factor. Although the underlying mechanisms are not clear, our results suggest that the inclusion of information about CAC presence in the LDCT report may represent a candidate factor to explain the decreased CV mortality observed in screened subjects of the ITALUNG trial, possibly resulting in intervention for patient care to prevent CV deaths. Further studies investigating whether prospective reporting and rating of CAC have independent impact on such interventions and CV mortality are worthy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Unit costs of screening CT colonography (CTC) can be useful for cost-effectiveness analyses and for health care decision-making. We evaluated the unit costs of CTC as a primary screening test for colorectal cancer in the setting of a randomized trial in Italy., Methods: Data were collected within the randomized SAVE trial. Subjects were invited to screening CTC by mail and requested to have a pre-examination consultation. CTCs were performed with 64- and 128-slice CT scanners after reduced or full bowel preparation. Activity-based costing was used to determine unit costs per-process, per-participant to screening CTC, and per-subject with advanced neoplasia., Results: Among 5242 subjects invited to undergo screening CTC, 1312 had pre-examination consultation and 1286 ultimately underwent CTC. Among 129 subjects with a positive CTC, 126 underwent assessment colonoscopy and 67 were ultimately diagnosed with advanced neoplasia (i.e., cancer or advanced adenoma). Cost per-participant of the entire screening CTC pathway was €196.80. Average cost per-participant for the screening invitation process was €17.04 and €9.45 for the pre-examination consultation process. Average cost per-participant of the CTC execution and reading process was €146.08 and of the diagnostic assessment colonoscopy process was €24.23. Average cost per-subject with advanced neoplasia was €3777.30., Conclusions: Cost of screening CTC was €196.80 per-participant. Our data suggest that the more relevant cost of screening CTC, amenable of intervention, is related to CTC execution and reading process.

Asymptomatic high-risk subjects, randomized in the intervention arm of the ITALUNG trial (1,406 screened for lung cancer), were enrolled for the ITALUNG biomarker study (n = 1,356), in which samples of blood and sputum were analyzed for plasma DNA quantification (cut off 5 ng/ml), loss of heterozygosity and microsatellite instability. The ITALUNG biomarker panel (IBP) was considered positive if at least one of the two biomarkers included in the panel was positive. Subjects with and without lung cancer diagnosis at the end of the screening cycle with LDCT (n = 517) were evaluated. Out of 18 baseline screen detected lung cancer cases, 17 were IBP positive (94%). Repeat screen-detected lung cancer cases were 18 and 12 of them positive at baseline IBP test (66%). Interval cancer cases (2-years) and biomarker tests after a suspect Non Calcific Nodule follow-up were investigated. The single test versus multimodal screening measures of accuracy were compared in a simulation within the screened ITALUNG intervention arm, considering screen-detected and interval cancer cases. Sensitivity was 90% at baseline screening. Specificity was 71 and 61% for LDCT and IBP as baseline single test, and improved at 89% with multimodal, combined screening. The positive predictive value was 4.3% for LDCT at baseline and 10.6% for multimodal screening. Multimodal screening could improve the screening efficiency at baseline and strategies for future implementation are discussed. If IBP was used as primary screening test, the LDCT burden might decrease of about 60%., (© 2017 UICC.)

Background: The accumulation of cyclin-dependent kinase inhibitor 2A (p16 ink4a ) protein in a cell is associated with neoplastic progression in precancerous cervical lesions. Dual staining for p16 ink4a and Ki-67 has been proposed as a triage test in cervical cancer screening for women who test positive for human papillomavirus DNA. In this study, interobserver reproducibility of the interpretation of this test was assessed., Methods: Forty-two immunostained, liquid-based cytology slides were divided into 2 sets and were interpreted by 17 to 21 readers from 9 different laboratories, yielding a total of 816 reports. Immunostaining results were classified as positive, negative, inconclusive, or inadequate. After evaluation of the first set of slides and before circulation of the second set, the results were discussed in a plenary meeting. The 10 slides with the most discordant results were evaluated again by selected expert cytopathologists., Results: The overall κ value was 0.612 (95% confidence interval [CI], 0.523-0.701), it was higher for the positive and negative categories (κ = 0.692 and κ = 0.641, respectively), and it was almost null for the inconclusive category (κ = 0.058). Considering only readers from laboratories with documented experience, the κ value was higher (κ = 0.747; 95% CI, 0.643-0.839) compared with nonexperienced centers (κ = 0.498; 95% CI, 0.388-0.616). The results were similar in both sets of slides (κ = 0.505 [95% CI, 0.358-0.642] and κ = 0.521 [95% CI, 0.240-0.698] for the first and second sets, respectively). Reinterpretation of the slides with the most discordant results did not provide any improvement (first evaluation, κ = 0.616 [95% CI, 0.384-0.866]; second evaluation, κ = 0.403 [95% CI, 0.182-0.643])., Conclusions: Dual staining for p16 ink4a and Ki-67 demonstrated good reproducibility, confirming its robustness, which is a necessary prerequisite for its adoption as a triage test in cervical cancer screening programs that use human papillomavirus DNA as a primary test. Cancer Cytopathol 2017;125:212-220. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Background and Objectives: A randomized trial was conducted in Tuscany, Italy, to evaluate the effectiveness of HPV vaccination for 25year old (yo) women who attend at the first time cervical cancer screening. The trial also evaluated immune response after vaccination, reductions of cytological abnormalities and the impact of vaccination on screening activity., Study Design: During 2010-2011, all 25 yo women who were invited to the Florence cervical cancer screening programme were also asked to participate in the trial. Enrolled women were randomized into study and control groups. Those in the study group were offered HPV vaccination after the usual Pap test. The cytology distribution and prevalence for any high risk (hr) HPV type were compared at the subsequent screening round in an intention-to-treat analysis. The impact of HPV vaccination was evaluated per protocol comparing vaccinated women with the control group., Results: Our results showed a reduction in HPV prevalence at recall for any hr-HPV type but it was not statistically significant, being 17.1% vs 21.4%, p=0.20 in the study and control groups, respectively. If we restricted the analysis to vaccinated women, strong reductions of the HPV 16,18,31,33,45 and HPV 31,33,45 infections were observed, being 5.3% vs 12.8%, p<0.01 and 2.1% vs 6.5%, p=0.02, respectively. Significant reductions for any hr-HPV infection and for HPV 16 infection were also observed in women HPV 16/18 negative at enrolment, being 12% vs 21.4%, p<0.01 and 0.6% vs 6.7%, p-value<0.01, respectively. In women hr-HPV negative at enrolment no infections due to HPV 16 or HPV 18 were observed and there was a big reduction for any hr-HPV infection (7.1% vs 21.4% p<0.01). A strong antibody response was observed not only for HPV 16 & 18 but also for their related types., Conclusions: Our findings suggest that HPV vaccination at the age 25 is beneficial if it is offered to hr-HPV negative women. Our data will assist in developing a cost effectiveness model for choosing the best strategy to integrate screening and vaccination for the coming years. Clinical trial registration number is NCT02296255., (Copyright © 2016 Elsevier B.V. All rights reserved.)

This review aims to highlight the importance of Quality Assurance for Laboratories performing HPV test for Cervical Cancer Screening. An HPV test, to be used as primary screening test, must be validated according to international criteria, based on comparison of its clinical accuracy to HC2 or GP5+/6+ PCR-EIA tests. The number of validated platforms is increasing and appropriate Quality Assurance Programs (QAPs) which can interrogate longitudinal robustness and quality are paramount. This document describes the following topics: (1) the characteristics of an HPV laboratory and the personnel training needs, to ensure an elevated quality of the entire process and the optimal use of the resources; (2) the Quality Assurance, as both internal (IQA) and external quality assessment (EQA) systems, to be implemented and performed, and the description of the existing EQAs, including limitations; (3) general considerations for an optimal EQA program for hrHPV primary screening Due to the importance of Quality Assurance for this field, international efforts are necessary to improve QA International Collaboration., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Lung cancer is the leading cause of cancer death worldwide and it would be essential to have effective tools to diagnose the disease in its early stages, to identify individuals at highest risk of developing the disease, and to set personalised therapies. The effectiveness of screening for lung cancer with low-dose CT (LDCT) in heavy smokers was demonstrated, in terms of reduction of cause-specific mortality, in recently published data by the study National Lung ScreeningTrial (NLST). In Europe, the introduction of LDCT as screening in individuals at risk is the object of a debate until the results of European randomized trials, expected in 2015-2016, are published. One problem is the high rate of calls for investigations when there is a noncalcified nodule, and it is therefore essential to be able to more accurately identify malignant nodules. The development of specific biomarkers appears to offer promising prospects. Recent advances in genetics and genomics have led to a series of studies aimed at the identification of molecular markers for the diagnosis, the assessment of the risk of developing lung cancer, the molecular characterisation of the different stages of the disease and the personalisation of therapy. Subjects enrolled in trials evaluating LCDT as a test for early detection of lung cancer represent the ideal population in which to study a combined bioinstrumental approach of screening (molecular test and LDCT). This paper reports on the state of knowledge on the possible use of biomarkers in the early detection of lung cancer and molecular analysis conducted within the project ITALUNG, a randomized controlled trial to assess the effect on tumour-specific mortality of LDCT, which provided a collection of biological materials from the subjects enrolled.

In this report, we present the results of cancer screening programmes in Italy for the years 2011-2012. This report is produced by the National centre for screening monitoring (ONS), together with the Italian professional multidisciplinary screening groups: GISMa (Italian group for mammographic screening), GISCor (Italian group for colorectal screening), and GISCi (Italian group for cervical screening). Since 2004, ONS has been monitoring and supporting Italian screening programmes, in accordance with a decree issued by the Ministry of Health. Multidisciplinary groups work with ONS and provide the know-how required to promote the quality of public health programmes. The following is a brief outline of the Italian screening programme setting: screening programmes (cervical, mammographic, colorectal) have been a Basic Healthcare Parameter (livello essenziale di assistenza, LEA) since 2001; guidelines are provided by the Ministry of Health's Department of Prevention in agreement with regional governments; regional governments are responsible for the organization, management, and quality assurance of screening programmes; since 2004, ONS has been responsible for monitoring and promoting screening programmes nationwide; the results of the screening programmes of each region are evaluated annually by the Ministry of Health in terms of coverage and impact.

Compared to spontaneous screening, an organized screening programme is characterized by the presence of protocols and recommendations for all stages including follow-up. Despite the availability of well-functioning screening programmes throughout the country, the follow-up protocol after an abnormal Pap test and negative colposcopy is not clearly defined in Italy, and there is no uniformity of indications. HPV testing for oncogenic human papillomavirus (hr-HPV) has a high negative predictive value (NPV) and high positive predictive value (PPV) for CIN2+ and its employment can reduce follow-up assessments. In order to provide indications about the management of women with ASC-US+ and the follow-up of women with cytological abnormalities and negative colposcopy, a literature analysis was carried out, taking into consideration European and American guidelines and good practice recommendations from the most important scientific associations and regulatory agencies. GISCi (Italian Group for Cervical Screening) drafted recommendations for the management of women with ASC-US, L-SIL, ASC-H, AGC, and H-SIL until their return to the routine screening interval. This protocol can be applied not only in the management of abnormal Pap smears in cytology-based programmes, but also in the management of abnormal Pap test triage after HPV positive test when HPV is the primary screening test. The protocols approved within the screening programmes must have an extensive consensus among all involved professionals, including any that women might meet outside the programme.

The Hybrid Capture 2 (HC2) test targets 13 human papillomavirus (HPV) types. Here, cross-reactivity with non-HC2-targeted HPV types is described. We aimed to define the proportion of HC2-positive women who had negative results with HC2-targeted HPV types and estimate its determinants and impact on women's health management. The New Technologies for Cervical Cancer (NTCC) trial was followed in two predetermined phases. Women in the experimental arm were tested for the presence of HPV DNA by HC2 following a sample collection in PreservCyt (first phase) or Digene specimen transport medium (STM) (second phase). HPV genotyping was performed on DNA samples from HC2-positive women by PCR with GP5(+)/GP6(+) primers and reverse line blot (RLB) hybridization. Untyped samples were submitted to direct sequencing or restriction fragment length polymorphism. Multivariate logistic regression analysis estimated the adjusted odds ratios (ORs) between the presence of HC2-targeted types and age, viral load, and type of transport medium. Out of 2,920 HC2-positive samples, 2,310 (79.1%) were positive on RLB for HC2-targeted types, 396 were positive (13.6%) for only non-HC2-targeted types (mostly represented by HPV-53, HPV-66, and HPV-70), and in 214 (7.33%) samples, no HPV types were detected. The probability of detecting HC2-targeted types increased with increasing viral load expressed as the relative light unit/positive-control specimen ratio (RLU/PC) (OR for unitary increase of log RLU/PC, 1.35; 95% confidence interval [CI], 1.30 to 1.42) and with STM versus PreservCyt (OR, 1.56; 95% CI, 1.25 to 1.84). If only the samples containing HC2-targeted types tested positive, the positive predictive value (PPV) would have increased from 7.0% (95% CI, 6.1% to 8.0%) to 8.4% (95% CI, 7.3 to 9.6), although 4.9% (95% CI, 2.4% to 8.8%) of cervical intraepithelial neoplasia grade 2(+) (CIN2(+)) cases would have been missed. In conclusion, STM use and an increased cutoff would reduce the HC2 analytical false-positive rate and increase the positive predictive value for high-grade CIN. The gain in clinical sensitivity by detecting non-HC2-targeted HPV types is limited.

Introduction: Recruitment and nodule management are critical issues of lung cancer screening with low-dose computed tomography (LDCT). We report subjects' compliance and results of LDCT screening and management protocol in the active arm of the ITALUNG trial., Methods: Three thousand two hundred six smokers or former smokers invited by mail were randomized to receive four annual LDCT (n = 1613) or usual care (n = 1593). Management protocol included follow-up LDCT, 2-[18F]fluoro-2-deoxy-D glucose positron emission tomography (FDG-PET), and CT-guided fine-needle aspiration biopsy (FNAB)., Results: One thousand four hundred six subjects (87%) underwent baseline LDCT, and 1263 (79%) completed four screening rounds. LDCT was positive in 30.3% of the subjects at baseline and 15.8% subsequently. Twenty-one lung tumors in 20 subjects (1.5% detection) were found at baseline, and 20 lung tumors in 18 subjects (0.5% detection) in subsequent screening rounds. Ten of 18 prevalent (55%) and 13 of 17 incident (76%) non-small-cell cancers were in stage I. Interval growth enabled diagnosis of lung cancer in 16 subjects (42%), but at least one follow-up LDCT was obtained in 741 subjects (52.7%) over the screening period. FDG-PET obtained in 6.5% of subjects had 84% sensitivity and 90% specificity for malignant lesions. FNAB obtained in 2.4% of subjects showed 90% sensitivity and 88% specificity. Positivity of both FDG-PET and FNAB invariably predicted malignancy. Surgery for benign lesions was performed on four subjects (10% of procedures) but followed protocol violations on three subjects., Conclusions: High-risk subjects recruited by mail who entered LDCT screening showed a high and stable compliance. Efficacy of screening is, however, weakened by low detection rate and specificity. Adhesion to management protocol might lessen surgery for benign lesions.

Objective: The aim of this study is to describe the prevalence of HPV types in invasive cervical cancers in Italy from 1996 to 2008., Methods: A pooled analysis of the three largest case series typed to date was performed. HPV typing was performed on paraffin-embedded slices. Molecular analyses were performed in four laboratories. Multivariate analyses were performed to test the associations between calendar time, age, and geographical area and the proportion of types 16/18., Results: Out of 574 cancers, 24 (4.2%) were HPV negative. HPV 16 and 18 were responsible for 74.4% (378/508) and 80.3% (49/61) of the squamous cancers and adenocarcinomas, respectively. Other frequent types were 31 (9.5%), 45 (6.4%), and 58 (3.3%) for squamous cancers and 45 (13.3%), 31, 35, and 58 (5.0%) for adenocarcinomas. The proportion of HPV 16 and/or 18 decreased with age (p-value for trend <0.03), while it increased in cancers diagnosed in more recent years (p-value for trend < 0.005)., Conclusions: The impact of HPV 16/18 vaccine on cervical cancer will be greater for early onset cancers. In vaccinated women, screening could be started at an older age without reducing protection.

Objective: this article presents a review of evidences about Human Papillomavirus (HPV) and cervical cancer in Italy, highlighting geographical differences., Design: two systematic reviews recently published were updated, one collecting studies on the prevalence of HPV types in Italy in the general population and the other collecting prevalence of HPV types in cervical pathologic samples.The search was updated to 31.10.2010 and performed exclusively in MedLine and references in retrieved papers., Main Outcome Measures: the prevalence of HPV types has been related with the incidence of cervical cancer and the spread of Pap tests and screening programs., Results: the prevalence high risk HPV types is 8%in studies with population-based random sample, with no significant difference between Centre-North and South-Islands, however, the prevalence is slightly higher in the South than the Centre-North for women up to 54 years of age, whereas in older women the ratio is reversed. HPV 16 is the most common type, while HPV 18 is less frequent, 5% and 1% respectively. The average of HPV 16 positivity is 64% and 68% in CIN2/3 and invasive cancer respectively, while the average of HPV 18 is 7% and 11% in CIN2/3 and invasive cancer respectively. There are no significant differences by geographical area.The incidence of invasive cervical cancer in Italy has been decreasing in recent years changing from 9.2 to 7.7 per 100,000 inhabitants in 10 years. The incidence is lower in South-Islands. Pap test coverage is over 80% in Centre-North and less than 60%in South-Islands., Conclusions: cervical cancer incidence is lower in Southern Italy, while the Pap test coverage is much higher in Centre-Northern Italy. This paradox, until now, has been interpreted as a consequence of a lower HPV prevalence in Southern than Northern regions. Recent studies on HPV prevalence do not confirm this hypothesis. Our interpretation is that in Southern Italy we are facing an epidemiologic scenario in transition where the low cancer incidence is the consequence of a low HPV prevalence in the previous decades, but new generations are experiencing a higher prevalence of HPV and will probably have higher risk of cervical cancer. The consequence may be an epidemic of cervical cancer in the next decades, if adequate screening programs are not implemented.

Randomized trials have produced sound evidence about the efficacy of screening with human papillomavirus (HPV) DNA tests in reducing cervical cancer incidence and mortality. We evaluated the clinical performance and reproducibility of the Abbott RealTime High Risk (HR) HPV test compared with that of the HR hybrid capture 2 (HC2) assay as assessed by a noninferiority score test. A random sample of 998 cervical specimens (914 specimens of cervical intraepithelial neoplasia less severe than grade 2 [

Background: HPV type distribution by cytological status represents useful information to predict the impact of mass vaccination on screening programs., Methods: women aged from 25 to 64 who attended cervical cancer screening in five different Italian regions were tested for HPV infection with Hybrid Capture II (HCII) low and high risk probes. Women repeating Pap-test upon unsatisfactory or positive results, or as a post-treatment and post-colposcopy follow-up analysis, were excluded from our study. High risk (HR) HPV positive samples were typed using GP5+/GP6+ primed PCR, followed by Reverse Line Blot for 18 high/intermediate risk HPV types, while low risk (LR) HPV positive samples were tested with type specific primers for HPV6 and HPV11., Results: 3410 women had a valid HCII and Pap-test. The prevalence of HR and LR infections was 7.0% and 3.6%, 29.1% and 13.7%, 68.1% and 31.9%, 60.0% and 0.0%, 65.0% and 12.0%, for negative, ASC-US, L-SIL, ASC-H and H-SIL cytology, respectively. The fraction of ASC-US+ cytology due to HPV 16 and 18 ranged from 11.2 (HPV 16/18 alone) to 15.4% (including HPV 16/18 in co-infection with other virus strains), and that due to HPV 6 and 11 ranged from 0.2% (HPV 6/11 alone) to 0.7% (including HPV 6/11 in co-infection with other LR virus strains)., Conclusions: mass vaccination with bivalent or quadrivalent HPV vaccine would modestly impact on prevalence of abnormal Pap-test in screening.

Background: The aim of this multicentric study was to identify human papillomavirus (HPV) type distribution in invasive cervical cancer and high-grade cervical intraepithelial neoplasia 2/3 (CIN2/3) in Italy., Methods: Cases were sampled through the electronic databases at the pathology units of eight centers in six regions from central and southern Italy. HPV types were detected from paraffin-embedded tissue samples and cervical specimens through amplification of HPV DNA with GP5+/GP6+ primers, followed by genotyping with reverse line blot (RLB). Untyped HPV-positive samples were sequenced. HPV-negative samples underwent nested PCR, followed by either RLB or sequencing. Finally, the remaining HPV-negative samples were amplified with primers targeting the virus E6 to E7 regions., Results: From 1,162 cases initially selected, 722 samples were further analyzed: 144 CIN2, 385 CIN3, 157 invasive squamous carcinomas, and 36 adenocarcinomas. Samples (6.9%) were HPV negative. The proportion of HPV16/18 was 60.8%, 76.6%, and 78.8% in CIN2, CIN3, and invasive cancers, respectively (P trend = 0.004). There was a significant decreasing trend of HPV16/18 with age in invasive cancers, going from 92% in women <35 years to 73% in women >55 years (P = 0.036). The proportion of coinfections was 16.8%, 15.5%, and 10.0% in CIN2, CIN3, and invasive cancers, respectively (P trend = 0.07)., Conclusions: The proportion of invasive cancers caused by HPV16/18 decreases with age at diagnosis., Impact: The absolute risk of an invasive cancer due to non-HPV16/18 in women under 35 is extremely low. This finding might prompt us to rise the age at which public HPV screening for vaccinated women should start., ((c)2010 AACR.)

Background: This multicenter study describes the type-specific prevalence of HPV infection in the general population from central and southern Italy, comparing the data with previously published Italian studies., Methods: Women aged from 25 to 65 who attended cervical cancer screening in five different Italian regions were tested for HPV infection with Hybrid Capture II (HCII) low and high risk probes. Women repeating Pap-test upon unsatisfactory or positive results, or as a post-treatment and post-colposcopy follow-up analysis, were excluded from our study. High risk (HR) HPV positive samples were typed using GP5+/GP6+ primed PCR, followed by Reverse Line Blot for 18 high/intermediate risk HPV types, while low risk (LR) HPV positive samples were tested with type specific primers for HPV6 and HPV11., Results: 3817 women had a valid HCII test: 350 of them (9.2%) were positive for HR probes, 160 (4.2%) for LR probes, while 57 women were positive for both. Multiple infections were detected in 97 HR HPV positive women. The most common types were HPV 16 (3%), 31 (1.2%), 51 (1%). HPV6 ranked fifth (0.6%), HPV18 ranked tenth (0.5%) and HPV11 sixteenth (0.3%).In Sardinia the prevalence of high-risk infection was 13%, significantly higher than the mean value (p < 0.00005).The distribution of the most frequent types did not significantly differ by centre (p = 0.187) and age (p = 0.085)., Conclusions: Because cervical cancer incidence and Pap test coverage is lower in southern than in northern Italy, a lower prevalence of high-risk infections in the general population was expected in the south. However, prevalence detected in this study for the south of the country is slightly but significantly higher than the rest of Italy. The consequence may be an epidemic of cervical cancer in the next decades if adequate screening programs are not implemented there.

The aim of this study was to evaluate the diagnostic value of a grid of molecular genetic markers detectable in sputum and plasma samples of individuals enrolled in a lung cancer screening program with low-dose CT. Subjects enrolled in the baseline screening round of the ITALUNG (randomised) screening trial were invited to provide biological specimens for molecular analysis (1356 subjects out of 1406). We included 98 subjects in this analysis. There was a highly statistically significant difference between proportion of subjects with a negative baseline CT screening test who were positive to allelic imbalance, and those with a non-calcified nodule (NCN greater than or equal to 5mm), the reason of recall for all suspects at CT Scan (chi(2): 22.9; P<0.0001). Allelic imbalance showed good performance for screening of NCN > or = 5 mm. In subjects recalled for NCN > or = 5 mm, LOH, K-ras mutations and high levels of free plasma DNA (>5ng/ml plasma) might be important to support clinical decision making for further follow-up and repeated screening. This study, embedded in an early diagnosis randomised trial, suggests that a multi-screening approach integrating imaging technique and a biomolecular marker panel is worth of further investigation., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Italy was the first European nation to offer free vaccination against human papillomavirus (HPV) types 16 and 18. The vaccination is actively encouraged and is available free of charge to 11-year-old girls. The introduction of new technologies such as HPV DNA testing and HPV vaccination requires cost-effectiveness analysis of cervical cancer strategies in Italy for both vaccinated and unvaccinated women., Methods: A calibrated Markov model was developed to describe the natural history of HPV infection and cervical carcinogenesis. We performed a microsimulation generating the life histories of 10 million women. Changes in these life histories occur as consequences of prevention strategies. We estimated costs of screening activities using an activity-based costing analysis. We assessed lifetime risk due to cervical cancer, lifetime costs and quality-adjusted life-expectancy (QALE) for 18 scenarios. Strategies varied by screening interval (three and five years), primary and triage test (Pap test and HPV DNA test), and HPV 16 and 18 vaccination., Results: The current screening policy (Pap test every three years) is more costly and less effective than HPV DNA test and Pap test triage every five years. For unvaccinated women an HPV DNA test every five years with a Pap test triage was cost-effective (ICER €5753/QALE). Vaccination followed by the same screening strategy was cost-effective (ICER €23,951/QALE) for women who are eligible to be vaccinated., Conclusions: Our findings strongly support changing the Pap screening policy to the use of HPV DNA as a primary test with Pap test triage for both vaccinated and unvaccinated women.

Human papillomavirus (HPV) is known to play an important etiological role in the genesis of cervical cancer, but only a very small proportion of infected women develop invasive cervical cancer. The purpose of cervical cancer prevention is early diagnosis of its precursors. The molecular detection of HPV DNA as a diagnostic test to cervical carcinogenesis gave a low positive predictive value as compared to the use of biomarkers. p16INK4a has been proposed as putative surrogate biomarkers that would allow identification of dysplastic cervical epithelia. Serial consecutive cervical smears were test for high-risk HPV stained with immunocytochemistry for p16INK4a and followed-up for 36 months. The aim of the study was to evaluate the immunohistochemical expression of pl6INK4a as a marker of progression risk in low-grade dysplastic lesions of the cervix uteri. In the present series, significant pl6 overexpression was observed in the group that progressed from low to high-grade squamous intraepithelial lesion when compared with the group that did not progress. In conclusion, overexpression of p16INK4a acts as potential biomarkers for cervical cancer progression from premalignant lesions.

Many different methods with different sensitivity and specificity have been proposed to detect the presence of high-risk human papillomavirus (HR HPV) in cervical samples. The HC2 is one of the most widely used. Recently, a new standardized PCR-based method, the AMPLICOR HPV test, has been introduced. Both assays recognize the same 13 HR HPV genotypes. The performances of these two commercially available assays were compared in 167 consecutive women (for a total of 168 samples) who presented at the Colposcopy Clinic either for a follow-up or for a diagnostic visit. Concordant results were found in 140/168 cervical samples (overall agreement, 83%; Cohen's kappa = 0.63). Twenty-eight samples gave discordant results: 20 were positive with the AMPLICOR HPV test and negative with the HC2 assay, and 8 were negative with the AMPLICOR HPV test and positive with the HC2 assay. The genotyping showed that no HR HPV was detected in the 8 HC2 assay-positive AMPLICOR HPV test-negative samples, while in 8/20 AMPLICOR HPV test-positive HC2 assay-negative samples, an HR HPV genotype was found. The AMPLICOR HPV test scored positive in a significantly higher percentage of subjects with normal Pap smears. All 7 cervical intraepithelial neoplasia grade 3 patients scored positive with the AMPLICOR HPV test, while 2 of them scored negative with HC2. Both tests had positive results in the only patient with squamous cell carcinoma. In conclusion, this study shows that the HC2 assay and the AMPLICOR HPV test give comparable results, with both being suitable for routine use. The differences noted in some cases may suggest a different optimal clinical use.

The purpose of this study was to determine the prognostic significance of the expression of p53 and Ki-67 in non-small cell lung cancer (NSCLC) using immunocytochemical detection. All consecutive NSCLC cases were selected for study, and, after surgery, a part of each tumor sample was frozen at -20 degrees C and stored for immunocytochemical studies. Overexpression of p53 was associated significantly with worse patient outcome in stage I disease, whereas no excess risk was evident in stage II and III cases. The same pattern was observed for Ki-67 expression. The excess risk in stage I cases with p53 and Ki-67 overexpression was observed only in adenocarcinoma. These findings are in agreement with other retrospective studies and support the hypothesis that p53 alteration may have different roles in adenocarcinoma and in squamous cell carcinoma, such as a carcinogenic factor for both cellular types but progression only for adenocarcinoma.

Within a large Italian randomized trial on new technologies for cervical cancer screening involving 7 laboratories with different levels of experience, an intralaboratory and interlaboratory quality control program for human papillomavirus (HPV) DNA testing by Hybrid Capture 2 (HC2; Digene, Gaithersburg, MD) was implemented. To monitor the hybridization and detection steps, target samples containing purified, concentration-defined, HPV DNA were introduced in each test run. Only 3 of 1,024 showed a mistake in a positive vs negative classification with a 1 relative light unit (RLU)/positive control specimen (PC) ratio cutoff. To monitor the preanalytic steps (particularly denaturation), blinded specimens (33 collected in PreservCyt (Cytyc, Boxborough, MA) and 36 in Specimen Transport Medium (STM, Digene) were centrally prepared, divided into aliquots, and sent to each laboratory. The multiple-rater scores for negative (<1 RLU/PC), low-positive (1 to <11 RLU/PC), and high-positive (> or =11 RLU/PC) samples, respectively, were 0.91, 0.60, and 0.69 with PreservCyt and 0.93, 0.87, and 0.90 with STM. Our data showed high reliability and reproducibility with HC2, with values higher for STM than ThinPrep (Cytyc) samples.

Background: The current study was conducted to evaluate the cost-effectiveness of triaging for colposcopy using human papillomavirus (HPV) testing., Methods: HPV tests were performed in a consecutive series of women who were referred for colposcopy for persistent atypical squamous cells of undetermined significance (ASCUS)-favor reactive (n = 35 women), ASCUS-favor squamous epithelial lesion (n = 164 women), atypical glandular cells of undetermined significance (n = 74 women), low-grade squamous epithelial lesion (n = 161 women), or high-grade squamous epithelial lesion (n = 78 women). The cost effectiveness of triaging women with ASCUS results using HPV testing was determined compared with the current protocol., Results: The sensitivity of HPV testing for cervical intraepithelial neoplasia > Grade 2 was very high. Cost analysis showed a moderate increase in cost with the addition of HPV triage., Conclusions: Because HPV testing is highly sensitive, it may be useful as an alternative to the current policy of 6-month repeat cytology for women with ASCUS., (2004 American Cancer Society)

The cost-effectiveness of qualifying ASCUS cases into two different subcategories, favoring a reactive (ASCUS-R) or dysplastic process (ASCUS-S), was evaluated at the Centro per lo Studio e la Prevenzione Oncologica of Florence in a prospective study. The study determined the positive predictive value (PPV) for histologically confirmed cervical intraepithelial neoplasia grade 2 (CIN2) or more (CIN>) severe lesion of the two ASCUS subgroups. ASCUS-S had a PPV (10.78%) comparable to low-grade squamous intraepithelial lesions (LSIL) (11.40%). For ASCUS-R cases, the recommendation of 6-mo repeat cytology prompting colposcopy in cases of persistent ASCUS or more severe cytology was also effective, as it selected a subgroup with a relatively high PPV (10.34%). The cost-effectiveness of a protocol based on ASCUS qualification was compared with two other possible options for nonqualified ASCUS cases: immediate colposcopy and colposcopy in persistent ASCUS at 6-mo repeat cytology. The detection rate of CIN2> was substantially higher using ASCUS qualification (35.9 vs 14.8 or 17.1). The cost per ASCUS subject was euro 24.99, 27.11, or 25.14 and that per CIN2> detected was euro 697, 1,831 or 1,470 for the three options, respectively. The evidence that ASCUS detection option implies a higher detection rate of CIN2> and subsequently a lower cost per CIN2> detection must be considered with caution and deserves confirmation by other comparative studies., (Copyright 2003 Wiley-Liss, Inc.)

Background: The results of blind reading of smears obtained with liquid-based cytology in patients previously screened by conventional cytology were compared., Material and Methods: Cases selected for the study were a consecutive series of 99 subjects undergoing colposcopy within the screening program of the Florence District. The Pap test samples were processed utilizing the Thin Prep 2000 (Cytyc Corporation, Boxborough, MA). The liquid-base cytology smears were randomly admixed and read by seven expert cytologists with more than 15 years of experience in Pap smear reading. For each case, a consensus diagnosis was created and considered as the definitive diagnosis. Cytologic reports in conventional and liquid-based cytology smears were compared by the kappa statistic to evaluate diagnostic agreement., Results: The study showed that the conventional and liquid-based cytology provide comparable cytologic reports and that the latter is not less sensitive than the former in detecting CIN2+ lesions of the cervix., Discussion: Such evidence suggests the feasibility of randomized studies comparing the two methods, which are needed before adopting liquid-based cytology as the current method when screening for cervical cancer.

In order to evaluate the agreement and accuracy of cervical (vaginal) cytologic diagnoses, 16 cytologists from a large laboratory in Florence, Italy, with experience ranging from 2 to 25 years, independently examined a set of 100 slides. A common reporting form based on a seven-category classification system was used. Concordance was calculated for each pairwise comparison between the 16 cytologists and between each cytologist and the target diagnosis. The values of the kappa statistic for the whole laboratory were .49 for the multiple raters comparison and .59 for the target diagnosis comparison, showing a relatively good degree of agreement.